3-[acetonyl; hydroxyethyl; and 2-(4-pyridyl)-ethyl]-1-(5-nitrofurfurylideneamino) hydntoin



United States Patent Ofi ice 3,097,202 Patented July 9, 1963 York NoDrawing. Filed Dec. 27, 1960, Ser. No. 78,315

4 Claims.

This invention relates to 1-(5-nitrofurfurylideneamino) hydantoinssubstituted in the 3-position of the hydantoin nucleus which may berepresented by the formula:

H; -o o in which R represents a member of the group consisting ofacetonyl, hydroxyethyl and 2-(4-pyridy1)ethyl.

These hydantoins are highly effective, relatively nontoxic systemicantimicrobial agents. They control systemic infections in animals causedby microorganisms such as Staphylococcus aureus and Eimeria tenella.Mice lethally infected with S. aureus are protected by the peroraladministration of a single dose of from 105-210 mg./ kg. of thesecompounds given post infection as a suspension incarboxylmethylcellulose. Chickens infected with E. tenella are protectedagainst the morbidity and mortality associated with coccidiosis provokedby that organism through the administration of these compoundsincorporated in their feed at a level of 0.022% by weight.

The dose of these compounds required to achieve therapeutic response isconsiderably less than that eliciting any unwanted toxic effect. In micetolerable doses of these compounds range from 7702200 mg./kg. Inchickens no evidence of toxic side elfect is seen at the level employedto combat coccidiosis.

I have found that the 3-[acetonyl; hydroxyethyl; and 2-(4-pyridyl)-ethyl] -1-(5 nitrofurfurylidenamino)hydantoins which I have inventedcan be prepared using materials which are readily available in the art.In genera! the methods which I have employed for the production of thesecompounds involve reacting a l-(alkylideneamino)hydantoin or a saltthereof with a compound containing a functional unit to introduce thesubstituent above defined as R and treating the formed3-R-substituted-l-(alkylideneamino)hydantoin under hydrolytic conditionsif necessary to free the 3-R-substituted-1-aminohydantoin for reactionwith 5-nitro-2-furaldehyde or a derivative thereof hydrolyzable thereto.

The method which I currently prefer to make the compounds of myinvention is dictated largely by the nature of the functional unit inthe compound employed for the introduction of the B-R-substituent. Whensaid functional unit is a halogen atom, such as chlorine, I have foundthe use of a salt of a I-(alkylideneamino)hydantoin, for instance thesodium salt, in the presence of an inert reaction medium composed of anorganic solvent such as pyridine or dimcthylformamide and theapplication of heat to the reaction mixture to be advantageous anddesirable for the production of the3-substituted-1-(alkylideneamino)hydantoin in good yield. Arepresentative schema is:

Hie-0 0 When said functional unit is a vinyl group, I have found thatthe salt form of a 1-(alkylideneamino)hydantoin is unnecessary and thatthe reaction proceeds readily and in good yield in the presence of asolvent and under the influence of heat. A representative schema Inorder to convert the I i-substituted-l-(alkylideneamino) hydantoinsdepicted in the above representative schema (I and II) to the desiredS-nitro furfurylidene compound, I have found it to be advantageous tohydrolyze them in an acidified aqueous medium such as aqueous mineralacid under the influence of heat and to add 5- nitrofuraldehyde or anequivalent thereof, such as S-nitrofuraldehyde diacetate which isreadily hydrolyzed under the reaction conditions, to the medium. Wherethe alkylidene component is volatile, steam distillation in the presenceof acid is an effective means for removing the volatile component fromthe reaction mixture and at the same time effecting hydrolysis.

The compounding of the 3-substituted-l-(S-nitrofurfurylidenamino)hydantoins of my invention in dosage form is readily carried out inaccordance with the pharmaceutical art. Tablets, suspensions, elixirs,and the like can be prepared using as carriers excipients and adjuvantscommon to the art.

In order that my invention may be available to and understood by thoseskilled in the art the following illustrative examples are supplied:

EXAMPLE I 3-[2-(4-Pyridyl)Ethyl]-1-(5-Nitrofurfurylideneamino) HydamoinA mixture of 157 g. (0.77 mole) of a l-benzylideneaminohydantoin, 500cc. of pyridine and g. (0.86 mole) of 4-vinylpyridine is refluxed for 30hours then poured into 3.5. l. of water. The solid that forms isfiltered, washed with water and dried at 110. There is obtained 203 g.(85%) of the intermediate compound. This product is steam distilled witha mixture of 300 cc. water and 80 cc. sulfuric acid to remove thebenzaldehyde. The solution is filtered through infusorial earth toclarify and then treated with an alcoholic solution of g. (0.7 mole) of5-nitro-2-furaldehyde. A small amount of nitrofurantoin that forms isremoved by filtration and the filtrate extracted with ether to removeany excess S-nitro- 2-furaldehyde. The resulting raffinate is basifiedwith ammonia to precipitate the crude l-(S-nitrofurfurylideneamino -3-2- (4 pyridyl ethyl] hydantoin. After filtering, washing with water,alcohol and ether, and air-drying, this material weighs 158 g. (70%). Itis purified by re-dissolving in dilute hydrochloric acid, treating withcharcoal and reprecipitating. A recovery of 87.5% is obtained.Recrystallization from 1:1 nitromethane:

methanol (10 cc./ 1 g.) using charcoal gives purified 3- [2 (4pyridyl)ethyl] 1 (5 nitrofurfurylidenamino) hydantoin decomposing at210-212.

In place of 5-nitro-2-furaldehyde, 5-nitro-2-furaldehyde diaoetate maybe used accompanied by heating to effect its hydrolysis.

EXAMPLE II 3-(2-Hydroxyetlzyl -1-(5-Nitr0furfurylideneamino) HydantoinTo a solution of 10.2 g. (0.05 mole) of lbenzylideneaminohydantoin in250 cc. of dimethylformamide is added 2.2 g. of 55% sodium hydride inmineral oil. When the sodium hydride has dissolved, 6.2 g. (0.0506 mole)of chloroethyl aoetate (JACS 46:766 (1924)) is added. The mixture isheated at 110120 overnight, then cooled. After filtering the salt, thedimethylform amide is removed under reduced pressure. The residue issteam distilled in the presence of dilute sulfuric acid until the soliddissolves. The aqueous solution is treated with charcoal, filtered andreacted with '7 g. of S-nitro- Z-furaldehyde in alcohol. After cooling,the yellow precipitate is filtered, Washed with water, alcohol and etherand dried at 110. There is obtained 11.5 g. (81.5%) of3-(2-hydroxy.ethyl)-1-(5-nitrofurfurylideneamino) hydantoin decomposingat about 233. Recrystallization from nitromethane using charcoal raisedthe decomposition point to 236-238".

For 5-nitro-2-iuraldehyde its diacetate may be substituted.

EXAMPLE III 3-Acet0nyl-1-(5-Nitr0furfurylideneamino)Hydantoin A mixtureof 40 g. (0.15 mole) of sodium nitrofurantoin, which may be prepared bytreating a suspension of in which R represents a member of the groupconsisting of acetonyl, hydroxyethyl and 2-(4-pyridyl)ethyl.

2. 3-[2-(4-pyridyl)ethyl]-1-(5 nitrofurfurylidene-amin0)-hydantoin.

3. 3-(2-hydroxyethyl) 1 (S-nitrofurfurylideneamino)hydantoin.

4. 3-acetonyl 1 (S-nitrofurfurylideneamino)hydantoin.

References Cited in the file of this patent UNITED STATES PATENTS Jacket al. June 27, 1961 OTHER REFERENCES Ware: Chemical Reviews, volume 46,pages 427-428 (1950).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,097,202 July 9, I963 Julian Getz Michels It is hereby certified thaterror appears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 1, line 29, for "carboxylmethylcellulose" read--carb0xymethylcellulose column 2, lines I to 7, the formula shouldappear as shown below instead of as in the patent:

CH=N-N-C=O NCH CH OCC H +Na C1 H CC=O column 2, line 52, after "of",second occurrence, strike out Signed and sealed this 21st day of January1964.

(SEAL) Attest: ERNEST W. SWIDER EDWIN L. REYNOLDS Attesting OfficerActing Commissioner of Patents UNITED STATES PATENT OFFICE CERTIFICATEOF CORRECTION Patent No. 3 ,097, 202 July 9, 1963 Julian Getz Michels Itis hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 1, line 29, for "carboxylmethylcellulose" readcarboxymethylcellulose column 2, lines 1 to 7 the formula should appearas shown below instead of as in the patent:

NCH CH OCC H +Na Cl column 2, line 52 after "of", second occurrence, 5trike ou Signed and sealed this 21st day of January 1964.

(SEAL) Attest: ERNEST W. SWIDER EDWIN L. REYNOLDS Acting Commissioner01" Attesting Officer Patents

1. A COMPOUND HAVING A CHEMOTHERAPEUTIC ACTIVITY UPON ORALADMINISTRATION AND REPRESENTED BY THE FORMULA: